Various methods are known as reactions for oxycarbonylating amino groups. As a reaction method for it, in which a piperazine derivative represented by general formula (1) is oxycarbonylated to produce an oxycarbonyl-substituted piperazine derivative represented by general formula (2)
(where R1, R2, R3 and R4 denote, respectively independently, i) a hydrogen atom, ii) an alkyl group with 1 to 4 carbon atoms, iii) an alkoxy group with 1 to 4 carbon atoms, iv) a halogen group, v) a carboxyl group, vi) a carbamoyl group, or vii) an N-alkylcarbamoyl group with 1 to 4 carbon atoms in its alkyl group; X denotes i) an alkyl group with 1 to 4 carbon atoms, ii) an alkenyl group with 2 to 4 carbon atoms, iii) an alkynyl group with 2 to 4 carbon atoms, iv) an aralkyl group not substituted in the aromatic ring, or substituted by an alkyl group with 1 to 4 carbon atoms or by an alkoxy group with 1 to 4 carbon atoms or by a halogen group, or v) an aryl group not substituted in the aromatic ring, or substituted by an alkyl group with 1 to 4 carbon atoms or by an alkoxy group with 1 to 4 carbon atoms or a halogen group; excluding the case where all of R1, R1, R3 and R4 denote a hydrogen atom respectively), the so-called Schotten-Baumann's method for performing a reaction in a mixed solvent of an organic solvent-water under an alkaline condition is employed. Detailed reaction conditions for the method are described in {“Protective Groups in Organic Synthesis,” Third Edition (John Wiley & Sons Inc., 1999), p. 531} and {Yukikagaku-Jikken-no-Tebiki 4—Gosei-Hanno—[II] (=Introduction to Experiments of Organic Chemistry 4—Synthetic Reactions [II])—(Kagaku Dojin, 1990), p. 24}. For example, in the former, benzyl chlorocarbonate is used for performing benzyloxy-carbonylation (Z-protection) in a sodium carbonate aqueous solution. Furthermore, in the latter, as an experimental example, the amino groups in kanamycin A sulfate were Z-protected using 1.3 eq. of Z-Cl. The reaction solvent was a mixed solvent of methanol/water=17/83 (ratio by weight). The yield was as low as 64%.
Moreover, there is a report that a reaction for monobenzyloxycarbonylation of a diamine by benzyl chlorocarbonate was performed in water-ethanol-dimethoxyethane solvent (the water content of the solvent=about 50 wt %) while the pH of the system was adjusted in 3.5 to 4.5 {Synthesis, 1032 (1984)}. However, also in this case, when the diamine was ethylene-diamine, the yield was as low as 71%, and it is reported that the yield declined with the increase of carbon atoms.
On the other hand, Reference Example 10 of JP2001-328938A was carried out using 0.25 molar time, based on the amount of 2-methylpiperazine, of Z-Cl in dichloromethane solvent at a very low temperature of −78° C. difficult to achieve industrially in general equipment. In this case, for inhibiting the side reaction by Z-Cl, 2-methylpiperazine more substrative than Z -Cl was used in a large amount for carrying out at a very low temperature. The yield based on the amount of Z-Cl was 85%, while the yield based on the amount of the substrate was 21%. In the case where an expensive substrate like an optically active substance is used, a method of 1 or more in the molar ratio of substrate/Z-Cl is economically disadvantageous. Furthermore, in {J. Chem. Soc., Perkin Trans. 1, 2973 (1998)}, acylation, especially Z-protection, benzoylation, tert-butoxycarbonylation (Boc-protection), etc. are performed using an N-mesyl-N-acylaniline deriveative, but since it is necessary to synthesize an oxycarbonylating agent separately, the method cannot be said to be industrially efficient.
So, in the case where a water-soluble piperazine derivative is made to react by a generally publicly known method of a liquid-liquid two-phase system, the yield of the oxycarbonyl -substituted piperazine derivative is as low as less than 50%. It was found that the byproduct in which both the two nitrogen atoms of the piperazine provided as the raw material are substituted by oxycarbonyl groups is produced more than the intended oxycarbonyl-substituted piperazine derivative. Therefore, it is demanded to create a simple method for producing an oxycarbonyl-substituted piperazine derivative at a high yield. It could therefore be advantageous to provide a process for producing an oxycarbonyl-substituted piperazine derivative at a high yield by oxycarbonylating a piperazine derivative.